EGFR modulators and uses thereof

1. A compound of Formula (VIII):

wherein

X 1 is O, NH, S, CH 2 , or CF 2 ;

R 1 and R 2 are independently selected from hydrogen, halo, C 1-6 alkyl, and C 1-6 haloalkyl;

R 3 is selected from halo, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, cyano, and nitro;

n is a number from zero to 4;

R 4 is selected from hydrogen, C 1-6 alkyl, C 3-7 cycloalkyl, and —NR 22 R 23 ;

wherein the alkyl or cycloalkyl is unsubstituted or substituted with hydroxyl or amino; and

wherein each R 22 and R 23 are independently selected from hydrogen and C 1-6 alkyl or R 22 and R 23 may be joined to form a 3 to 10 membered ring;

R 5 is selected from hydrogen and C 1-6 alkyl;

R 6 is selected from hydrogen, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, hydroxyl, cyano, and nitro;

R 7 is selected from hydrogen, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, hydroxyl, cyano, and nitro;

R 8 is selected from hydrogen, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, hydroxyl, cyano, and nitro;

Q is CR 9 or N;

R 9 is selected from hydrogen, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, hydroxyl, cyano, and nitro;

R 11 is selected from hydrogen and C 1-6 alkyl;

R 12 is selected from hydrogen and C 1-6 alkyl;

R 13 is selected from hydrogen, C 1-6 alkyl, C 1-6 acyl, SO 2 —C 1-6 alkyl, C 3-7 cycloalkyl, and C 6-20 aryl,

wherein each alkyl or aryl is unsubstituted or substituted with hydroxyl, C 1-6 alkoxy, or halo; and

—NR 18 R 19 is

or

wherein R 10 is selected from hydrogen and C 1-6 alkyl;

R 15 is unsubstituted methyl, or is C 2-4 alkyl unsubstituted or substituted with hydroxy, methoxy, or halo; and

m is 1 or 2;

or R 19 and R 9 taken together form a 5- or 6-membered heteroaryl ring optionally substituted with C 1-6 alkyl that is unsubstituted or substituted with amino, hydroxyl, or halo; and R 18 is hydrogen or C 1-6 alkyl, or is absent to satisfy valency of the heteroaryl ring;

provided that neither of R 6 or R 7 is methoxy when —NR 18 R 19 is

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , wherein the compound is a compound of Formula (Ia) or (Ib):

wherein

R 1 and R 2 are independently selected from hydrogen, halo, C 1-6 alkyl, and C 1-6 haloalkyl;

R 3 is selected from halo, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, cyano, and nitro;

n is a number from zero to 4;

R 4 is selected from hydrogen, C 1-6 alkyl, C 3-7 cycloalkyl, and —NR 22 R 23 ;

wherein the alkyl or cycloalkyl is unsubstituted or substituted with hydroxyl or amino; and

wherein each R 22 and R 23 are independently selected from hydrogen and C 1-6 alkyl or R 22 and R 23 may be joined to form a 3 to 10 membered ring;

R 5 is selected from hydrogen and C 1-6 alkyl;

R 6 is selected from hydrogen, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkoxy, C 1-6 haloalkoxy, hydroxyl, cyano, and nitro;

R 7 is selected from hydrogen, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkoxy, C 1-6 haloalkoxy, hydroxyl, cyano, and nitro;

R 8 is selected from hydrogen, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, hydroxyl, cyano, and nitro;

Q is CR 9 or N;

R 9 is selected from hydrogen, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, hydroxyl, cyano, and nitro;

R 10 is selected from hydrogen and C 1-6 alkyl;

a is one or two;

Ring A is an aromatic ring;

R 20 and R 21 are independently selected from hydrogen and C 1-6 alkyl; wherein alkyl is unsubstituted or substituted with amino, hydroxyl, or halo; wherein R 21 may not present to satisfy valency;

R 11 is selected from hydrogen and C 1-6 alkyl;

R 12 is selected from hydrogen and C 1-6 alkyl; and

R 13 is selected from hydrogen, C 1-6 alkyl, C 1-6 acyl, SO 2 —C 1-6 alkyl, C 3-7 cycloalkyl, and C 6-20 aryl,

wherein each alkyl or aryl is unsubstituted or substituted with hydroxyl, C 1-6 alkoxy, or halo;

or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 , wherein the compound is a compound of Formula (II):

wherein

R 1 and R 2 are independently selected from hydrogen, halo, C 1-6 alkyl, and C 1-6 haloalkyl;

R 3 is selected from halo, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, cyano, and nitro;

n is a number from zero to 4;

R 4 is selected from hydrogen, C 1-6 alkyl, C 3-7 cycloalkyl, and —NR 22 R 23 ;

wherein the alkyl or cycloalkyl is unsubstituted or substituted with hydroxyl or amino; and

wherein each R 22 and R 23 are independently selected from hydrogen and C 1-6 alkyl or R 22 and R 23 may be joined to form a 3 to 10 membered ring;

R 5 is selected from hydrogen and C 1-6 alkyl;

R 6 is selected from hydrogen, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkoxy, C 1-6 haloalkoxy, hydroxyl, cyano, and nitro;

R 7 is selected from hydrogen, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkoxy, C 1-6 haloalkoxy, hydroxyl, cyano, and nitro;

R 8 is selected from hydrogen, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, hydroxyl, cyano, and nitro;

Q is CR 9 or N;

R 9 is selected from hydrogen, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, hydroxyl, cyano, and nitro;

R 10 is selected from hydrogen and C 1-6 alkyl;

R 11 is selected from hydrogen and C 1-6 alkyl;

R 12 is selected from hydrogen and C 1-6 alkyl; and

R 13 is selected from hydrogen, C 1-6 alkyl, and C 6-20 aryl, wherein each alkyl or aryl is unsubstituted or substituted with hydroxyl, C 1-6 alkoxy, or halo;

or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1 , wherein X 1 is O or NH.

5. The compound of claim 1 , wherein R 11 is hydrogen.

6. The compound of claim 1 , wherein R 12 is hydrogen.

7. The compound of claim 1 , wherein R 1 and R 2 are each hydrogen.

8. The compound of claim 1 , wherein n is zero.

9. The compound of claim 1 , wherein —NR 18 R 19 is

10. The compound of claim 9 , wherein R 1 ° is methyl.

11. The compound of claim 1 , wherein R 13 is hydrogen.

12. The compound of claim 1 , wherein R 13 is C 1-6 alkyl substituted with hydroxyl or halo.

13. The compound of claim 1 , wherein R 6 is hydrogen.

14. The compound of claim 1 , wherein R 7 is hydrogen or methoxy.

15. The compound of claim 1 , wherein R 8 is hydrogen.

16. The compound of claim 1 , wherein Q is N.

17. The compound of claim 1 , wherein Q is CR 9 .

18. The compound of claim 17 , wherein R 9 is hydrogen or fluoro.

19. The compound of claim 1 , wherein R 19 and R 9 together form a 5- or 6-membered ring optionally substituted with C 1-6 alkyl that is unsubstituted or substituted with amino.

20. The compound of claim 1 selected from the group consisting of:

N-(3-((2-((4-(4-methylpiperazin-1-yl)phenyl)amino)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)phenyl)acrylamide

N-(3-((2-((6-(4-methylpiperazin-1-yl)pyridin-3- yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)oxy)phenyl)acrylamide

N-(3-((2-((3-fluoro-4-(4-methylpiperazin-1- yl)phenyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)oxy)phenyl)acrylamide

N-(3-((7-(hydroxymethyl)-2-((4-(4-methylpiperazin-1- yl)phenyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)oxy)phenyl)acrylamide

N-(3-((7-(hydroxymethyl)-2-((6-(4-methylpiperazin-1- yl)pyridin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)oxy)phenyl)acrylamide

N-(3-((2-((3-fluoro-4-(4-methylpiperazin-1- yl)phenyl)amino)-7-(hydroxymethyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)oxy)phenyl)acrylamide

N-(3-((7-(2-fluoroethyl)-2-((4-(4-methylpiperazin-1- yl)phenyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)oxy)phenyl)acrylamide

N-(3-((2-(( 1-(2-(dimethylamino)ethyl)-1H-indol-5- yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)oxy)phenyl)acrylamide

N-(3-((2-(2-((dimethylamino)methyl)quinolin-6- yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)oxy)phenyl)acrylamide

N-(3-((5-cyclopropyl-2-((4-(4-methylpiperazin-1- yl)phenyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)oxy)phenyl)acrylamide

N-(3-((5-cyclopropyl-2-((3-fluoro-4-(4-methylpiperazin- 1-yl)phenyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)oxy)phenyl)acrylamide

N-(3-((2-((4-(4-methylpiperazin-1-yl)phenyl)amino)-5- (pyrrolidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)oxy)phenyl)acrylamide

N-(3-((2-((3-fluoro-4-(4-methylpiperazin-1- yl)phenyl)amino)-5-(pyrrolidin-1-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)oxy)phenyl)acrylamide

N-(3-((5-(2-hydroxyethyl)-2-((4-(4-methylpiperazin-1- yl)phenyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)oxy)phenyl)acrylamide

N-(3-((2-((3-fluoro-4-(4-methylpiperazin-1- yl)phenyl)amino)-5-(2-hydroxyethyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)oxy)phenyl)acrylamide

N-(3-((5-((dimethylamino)methyl)-2-((4-(4- methylpiperazin-1-yl)phenyl)amino)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)oxy)phenyl)acrylamide

N-(3-((5-((dimethylamino)methyl)-2-((3-fluoro-4-(4- methylpiperazin-1-yl)phenyl)amino)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)oxy)phenyl)acrylamide

N-(3-((5-(dimethylamino)-2-((4-(4-methylpiperazin-1- yl)phenyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)oxy)phenyl)acrylamide

N-(3-((5-(dimethylamino)-2-((3-fluoro-4-(4- methylpiperazin-1-yl)phenyl)amino)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)oxy)phenyl)acrylamide

N-(3-((5-(2-(dimethylamino)ethyl)-2-((4-(4- methylpiperazin-1-yl)phenyl)amino)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)oxy)phenyl)acrylamide

N-(3-((5-(2-(dimethylamino)ethyl)-2-((3-fluoro-4-(4- methylpiperazin-1-yl)phenyl)amino)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)oxy)phenyl)acrylamide

N-(3-((5-(aziridin-1-yl)-2-((4-(4-methylpiperazin-1- yl)phenyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)oxy)phenyl)acrylamide

N-(3-((5-(aziridin-1-yl)-2-((3-fluoro-4-(4- methylpiperazin-1-yl)phenyl)amino)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)oxy)phenyl)acrylamide

N-(3-((5-(azetidin-1-yl)-2-((4-(4-methylpiperazin-1- yl)phenyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)oxy)phenyl)acrylamide

N-(3-((5-(azetidin-1-yl)-2-((3-fluoro-4-(4- methylpiperazin-1-yl)phenyl)amino)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)oxy)phenyl)acrylamide

N-(3-((2-((4-(4-methylpiperazin-1-yl)phenyl)amino)-5- (piperidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)oxy)phenyl)acrylamide

N-(3-((2-((3-fluoro-4-(4-methylpiperazin-1- yl)phenyl)amino)-5-(piperidin-1-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)oxy)phenyl)acrylamide

N-(3-((7-cyclopropyl-2-((4-(4-methylpiperazin-1- yl)phenyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)oxy)phenyl)acrylamide

N-(3-((7-cyclopropyl-2-((3-fluoro-4-(4-methylpiperazin- 1-yl)phenyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)oxy)phenyl)acrylamide

N-(3-((2-((4-(4-methylpiperazin-1-yl)phenyl)amino)-7- (methylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)oxy)phenyl)acrylamide

N-(3-((2-((3-fluoro-4-(4-methylpiperazin-1- yl)phenyl)amino)-7-(methylsulfonyl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl)oxy)phenyl)acrylamide

N-(3-((7-acetyl-2-((4-(4-methylpiperazin-1- yl)phenyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)oxy)phenyl)acrylamide

N-(3-((7-acetyl-2-((3-fluoro-4-(4-methylpiperazin-1- yl)phenyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)oxy)phenyl)acrylamide

N-(3-(2-(4-(1-(2-fluoroethyl)azetidin-3-ylamino)-2- methoxyphenylamino)-7H-pyrrolo[2,3-d]pyrimidin-4- yloxy)phenyl)acrylamide

N-(3-(2-(4-(1-(2-fluoroethyl)azetidin-3-ylamino)-2- methoxyphenylamino)-7H-pyrrolo[2,3-d]pyrimidin-4- ylamino)phenyl)acrylamide; and

N-(3-((2-((2-(piperidin-1-ylmethyl)quinolin-6- yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)oxy)phenyl)acrylamide

and pharmaceutically acceptable salts thereof.

21. The compound of claim 1 , wherein the compound is a compound of Formula (VII):

wherein

R 1 and R 2 are independently selected from hydrogen, halo, C 1-6 alkyl, and C 1-6 haloalkyl;

R 8 is selected from halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, hydroxyl, cyano, and nitro;

R 10 is C 1-6 alkyl; and

R 13 is hydrogen or C 1-6 alkyl;

or a pharmaceutically acceptable salt thereof.

22. The hydrochloride salt of the compound N-(3-((2-((3-fluoro-4-(4-methylpiperazin-1-yl)phenyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)phenyl)acrylamide.

23. A pharmaceutical composition comprising (a) at least one compound of claim 1 or a pharmaceutically acceptable salt thereof, and (b) a pharmaceutically acceptable carrier or excipient.